DESCRIPTION: p53 can be viewed as a integrator of stress signals and responses in cells. The widespread attention that p53 has earned stems both from the fact that it is a tumor suppressor gene frequently mutated in many human tumor types, and that it regulates important processes in the cell. DNA tumor virus (SV40, Ad, HPV) modulate p53 function. An important question not yet answered in the p53 field is: what is upstream of p53 and how does it function to signal p53. The overall goals of this application are to elucidate how cells signal to and control the function of p53. Multiple aims deal with evaluating further the role of phosphorylation in regulating p53 function. They include investigating the influence of phosphorylation on p53:Mdm2 interactions, the role of TFIIH associated CAK/p36 kinase in modulating p53 function and the role of phosphorylation events in the c terminus of p53 on p53 function. Other aims are directed at investigating the significance of the Ref-1:p53 interaction, the role of cyclin G, a p53 responsive gene in modulating p53 effects on cells and the role of p53 in DNA replication/repair.